The Rise and Fall of SIG-001
A Shielded Cell Therapy for Hemophilia A
Introduction: The Quest for a Functional Cure
For centuries, hemophilia A has presented a formidable challenge to the medical community. This inherited bleeding disorder, affecting approximately 1 in 5,000 males, arises from mutations in the F8 gene that lead to deficient production of factor VIII (FVIII), a crucial blood-clotting protein 1 . Traditional treatments have centered on regular factor replacement therapies, which, while life-changing, come with significant limitations: substantial treatment burden, unpredictable kinetics leading to breakthrough bleeds, risk of inhibitor development, and potential for chronic joint disease 1 .
The dream of a "functional cure" – a one-time treatment providing sustained FVIII production – has driven scientific innovation for decades. Enter SIG-001, an innovative shielded cell therapy that promised to revolutionize hemophilia A treatment by turning the human body into its own FVIII production facility.
Genetic Basis
Hemophilia A results from mutations in the F8 gene located on the X chromosome, leading to deficient factor VIII production.
Treatment Burden
Traditional therapies require frequent intravenous infusions, creating significant lifestyle limitations for patients.
The Science Behind Shielded Living Therapeuticsâ„¢
A Revolutionary Approach to Chronic Disease
Sigilon Therapeutics developed a platform aimed at addressing one of the most significant challenges in cell therapy: immune rejection. The company's Shielded Living Therapeuticsâ„¢ platform represented a novel strategy for treating chronic diseases through engineered human cells that could produce therapeutic proteins continuously 1 5 .
Shielded Living Therapeuticsâ„¢
A novel platform designed to protect engineered cells from immune rejection while enabling continuous therapeutic protein production.
Overcoming Historical Challenges
Previous attempts at encapsulated cell therapies had stumbled on a critical obstacle: pericapsular fibrotic overgrowth (PFO). This phenomenon occurred when the host's immune system recognized the foreign material, triggering a foreign body response that resulted in scar tissue forming around the implants. This fibrotic overgrowth ultimately limited efficacy and durability of the treatment by restricting nutrient flow and potentially compromising the viability of the encapsulated cells 1 .
Sigilon's Innovation
Sigilon's innovation lay in proprietary small molecules conjugated to alginate biomaterials specifically designed to avoid PFO 1 . The dual-layer sphere architecture provided an inner compartment to support cell function and an outer layer intended to shield the cells from the host's immune system while preventing fibrosis 1 .
SIG-001: From Concept to Clinical Trial
Design and Mechanism of Action
SIG-001 consisted of a buffered suspension of 1.5 mm alginate spheres – approximately the size of a ballpoint pen tip – encapsulating thousands of human cells engineered to express human FVIII 1 . These spheres were designed to be implanted into the peritoneal cavity during a laparoscopic procedure, where they would theoretically remain functional for extended periods, continuously releasing FVIII into the bloodstream .
The therapy demonstrated promising results in preclinical studies with dose-dependent FVIII production.
Clinical Trial Design
The first-in-human Phase 1/2 trial (SIG-001-121, NCT04541628) was designed as a multi-center, open-label study with sequential, dose-escalating cohorts 1 . The planned enrollment was up to 18 participants, including adults (≥18 years) with severe or moderately severe hemophilia A (≤2% FVIII activity) who had experienced at least 150 exposure days to FVIII products 1 .
| Trial Aspect | Design Specification |
|---|---|
| Study Type | Multi-center, open-label, dose-escalation |
| Planned Enrollment | Up to 18 participants |
| Patient Population | Adult males with severe/moderately severe hemophilia A (≤2% FVIII activity) |
| Prior Treatment Requirement | ≥150 exposure days to FVIII products |
| Key Exclusion | Current or past FVIII inhibitors |
| Administration | Laparoscopic implantation into peritoneal cavity |
| Follow-up Period | 5 years post-administration |
18
Planned Participants
5
Years Follow-up
150+
Prior Exposure Days Required
The Clinical Setback: Unforeseen Complications
Inhibitor Development and Clinical Hold
In July 2021, the promising trajectory of SIG-001 hit a significant roadblock. The U.S. Food and Drug Administration (FDA) placed the Phase 1/2 study on clinical hold following Sigilon's report of a serious adverse event 2 6 .
Of the three patients who had been dosed with SIG-001, the patient receiving the highest dose developed antibodies that inhibited FVIII – a well-known complication of FVIII replacement therapy called "inhibitor development" 2 6 . These antibodies bind to FVIII and block its activity, potentially rendering treatments ineffective.
The Fibrosis Discovery
In late 2021, further complications emerged when a laparoscopic retrieval procedure was performed on the affected patient at the direction of the study investigator 4 5 . Upon inspection, researchers made a troubling discovery: the implanted spheres had become scarred and fibrosed, with the cells inside no longer viable 3 4 .
This fibrosis represented the very phenomenon – pericapsular fibrotic overgrowth – that Sigilon's proprietary biomaterials were specifically designed to prevent 1 4 . The observation directly contradicted one of the platform's key proposed advantages – resistance to foreign body response.
Timeline of SIG-001 Clinical Trial Setbacks
The Scientist's Toolkit: Key Components of the SIG-001 Platform
The development and testing of SIG-001 relied on numerous sophisticated technologies and reagents. Below are some of the key components that formed the foundation of this investigational therapy.
| Research Tool | Function in SIG-001 Development |
|---|---|
| Alginate Biomaterials | Natural seaweed-derived polymer forming the primary matrix for cell encapsulation 1 |
| Afibromerâ„¢ | Sigilon's proprietary synthetic biomaterial designed to minimize fibrotic response 6 |
| F8 Gene Construct | Genetic material encoding human factor VIII protein for cellular engineering 1 |
| Human Cell Lines | Allogeneic cells engineered to produce and secrete functional FVIII 1 |
| Anti-FVIII Antibody Assays | Critical for detecting inhibitor development in treated patients 2 6 |
| Factor VIII Activity Assays | Both one-stage and chromogenic methods to quantify FVIII production 1 |
| Proprietary Small Molecules | Conjugated to alginate to prevent pericapsular fibrotic overgrowth 1 |
Biomaterials
Alginate-based materials formed the protective matrix for cell encapsulation.
Genetic Engineering
Cells were engineered to produce and secrete functional FVIII.
Analytical Tools
Specialized assays monitored therapy performance and safety.
Aftermath and Implications
Strategic Reprioritization
In December 2021, following these clinical setbacks, Sigilon Therapeutics announced a strategic reprioritization of its pipeline 3 7 . The company revealed it would shift its focus from the hemophilia A program to other investigational therapies, including SIG-005 for mucopolysaccharidosis type I (MPS-1) and SIG-002 for type 1 diabetes being developed in partnership with Eli Lilly 3 7 .
Accompanying this reprioritization was a workforce reduction of approximately 38%, mainly affecting research, manufacturing, and administrative roles 3 . Rogerio Vivaldi, Sigilon's President and CEO, acknowledged that there had been "key learnings" from the Phase 1/2 trial of SIG-001 that would inform the development of their broader platform 3 7 .
New Focus Areas
- SIG-005 for MPS-1 In Development
- SIG-002 for Type 1 Diabetes Partnership with Eli Lilly
Lessons for the Field
Immune System Challenges
Despite sophisticated shielding technologies, the immune system proved capable of mounting both a humoral response (inhibitor development) and a cellular response (fibrosis) against the therapy.
Biomaterial Complexity
Creating materials that truly evade immune recognition and fibrotic responses remains an elusive goal, despite advanced engineering approaches.
Dose-Escalation Caution
The fact that the adverse events occurred in the highest-dosed patient highlights the importance of cautious dose escalation in first-in-human trials.
Conclusion: The Future of Hemophilia Treatment
While SIG-001 may have stumbled in its clinical application, its development represented a bold step forward in the quest for functional cures for hemophilia A. The concept of creating a bioreactor within the patient's body to continuously produce the missing clotting factor remains compelling, even if the execution proved challenging.
Future Directions
The field of hemophilia treatment continues to evolve, with other innovative approaches showing promise. For instance, BioMarin's gene therapy valoctocogene roxaparvovec received RMAT (Regenerative Medicine Advanced Therapy) designation from the FDA and demonstrated significant reductions in annualized bleeding rates and factor VIII usage in clinical trials 2 .
The story of SIG-001 serves as a reminder that medical innovation is rarely a straight path. Setbacks and unexpected challenges are inherent to the process of scientific advancement. What appears to be a failure in one context often provides crucial insights that inform future success. As researchers continue to build upon these lessons, the dream of a functional cure for hemophilia A endures, propelled by both achievements and setbacks along the way.